FDA is showing for the second time in as many weeks that all things are possible when it comes to clearing targeted oncologics with compelling evidence. The agency cleared Pfizer’s Xalkori (crizotinib) for late-stage non-small cell lung cancer Aug. 26, just under five months from submission and based on early stage evidence.

The ALK inhibitor is indicated for treatment of patients with locally advanced or metastatic non-small cell lung cancer who express the abnormal anaplastic lymphoma kinase gene, who can be identified with a companion diagnostic.

Xalkori is the second approval of an oncologic with a companion diagnostic this year, FDA says.

On Aug. 17, FDA approved Roche/Genentech’s metastatic melanoma therapy Zelboraf (vemurafenib), for patients with the V600E BRAF mutation selected by a companion diagnostic, in 3.6 months (Also see "Zelboraf Approval Hastened By FDA Officials Impressed With Early Efficacy" - Pink Sheet, 22 August, 2011.). And earlier this year, Johnson & Johnson’s hormone-refractory prostate cancer drug Zytiga (abiraterone) was cleared in 4.3 months. Oncology approvals can come even faster, especially when there is survival data: Sanofi’s Jevtana (cabazitaxel) was approved for HRPC in 2.6 months in 2010.

The crizotinib clearance is all the more notable for the speed of the rest of the development process, and as a submission based primarily upon Phase I data (Also see "Fast As A Whip, Pfizer Files Personalized Lung Cancer Drug Crizotinib" - Pink Sheet, 12 January, 2011.).

The EML4-ALK fusion gene was identified as a biomarker for NSCLC in 2007. Pfizer revamped its plans for crizotinib – then being studied for MET-inhibition properties – and submitted it for approval March 30, roughly four years since conceptualization.

At a May press briefing, Pfizer’s Mace Rothenberg, senior VP of clinical development and medical affairs for the Oncology Business Unit, noted that the process had been cut roughly in half for this drug, from eight to 10 years to four to five.

The Phase I data made quite an impression when it was presented at the American Society of Clinical Oncology annual meeting in 2010. Over 90% of the patients positive for the EML4-ALK fusion gene showed tumor shrinkage (Also see "Crizotinib Holds Promise For Lung Cancer, And For Pfizer Oncology" - Pink Sheet, 14 June, 2010.).

Updated Phase I data from a study extension was presented at ASCO this year, showing that of the 82 ALK-positive patients, 77% were alive at one year and 64% at two years (Also see "Survival Data For Pfizer's Crizotinib Appears Promising, Positioning It For Accelerated Approval" - Pink Sheet, 19 May, 2011.).

Such strong signs of activity led Pfizer to skip most Phase II work and start a randomized Phase III trial, PROFILE 1007, which is still ongoing and will serve as the confirmatory trial for the accelerated approval. The company also ran a companion single-arm Phase II study, PROFILE 1005, which was added to the NDA.

FDA’s news release on the approval notes that its decision was based on the objective response rates seen in “two multi-center, single-arm studies enrolling a total of 255 patients.” In one study, the ORR was 50% with a median response duration of 42 weeks. In the other, ORR was 61% with median duration of 48 weeks.

Simultaneous to the drug approval, FDA cleared the companion diagnostic from Abbott Molecular, the Vysis ALK Break Apart FISH Probe Kit – also well in advance of the test’s Sept. 28 user fee review date. The agency based that approval on data from one of the two studies.

The diagnostic can identify the roughly 1% to 7% of NSCLC patients who have the ALK gene abnormality (typically non-smokers) – and while that is a small proportion for the drug, the diagnostic will need wide use for identification. Ensuring utilization could be the biggest challenge for the sponsors. Diagnostic testing is not well established in lung cancer, and the testing can be difficult (Also see "NSCLC Market Snapshot: Promising Biomarkers, Testing Challenges" - Pink Sheet, 30 May, 2011.).

Still, the crizotinib approval is sure to become a shining example of how having a molecularly identified population can grease the skids at FDA.

And it could in turn be a harbinger of a better outlook for personalized medicine projects at FDA. Pfizer’s Rothenberg, at a press briefing in October 2010, commented that crizotinib could be a “catalyst to really allow us to understand a regulatory pathway for bringing diagnostics and therapeutics forward together.” It is Pfizer’s first omcology product with a companion diagnostic, the firm reported in announcing the approval.

The agency released a draft guidance on co-development of drugs and companion diagnostics in July, long after it was anticipated (Also see "FDA Releases Companion Dx Guidance Broad In Scope, Limited In Detail" - Pink Sheet, 18 July, 2011.).

Xalkori is immediately available through certain specialty pharmacies; Pfizer has hotlines to help patients source testing and drug availability. The company is offering co-pay assistance through its Pfizer First Resource patient assistance program.

By Mary Jo Laffler

Pfizer’s Crizotinib Eases Past FDA With Targeted Population

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